Percutaneous transluminal coronary angioplasty (PTCA) is a common procedure for treating atherosclerosis, but its efficacy is limited because of the occurrence of restenosis within 3-6 months after angioplasty. Restenosis is induced by the remodeling of the vessel wall and/or the accumulation of cells and extracellular matrix (ECM) in the intimal layer. Therefore, the matrix metalloproteinase (MMP) system may be a potential therapeutic target for the treatment of restenosis or atherosclerosis. Cordycepin is reported to possess many pharmacological activities including immunological stimulating, anti-cancer, antioxidant, and anti-inflammatory activities. The effect of cordycepin on restenosis has not yet been clearly elucidated. Therefore, in the present study, we tested the role of cordycepin on the MMP system in vascular smooth muscle cells. In the carotid artery of a balloon-injured Sprague-Dawley (SD) rat, neointimal formation was reduced by treatment with cordycepin (20 microM/day, i.p), which inhibited the proliferation of rat aortic smooth muscle cells (RaoSMCs). To investigate the mechanism by which cordycepin inhibits the remodeling of the vessel wall and/or the accumulation of cells and ECM, we examined the activation of MMP systems in collagen type I-activated RaoSMCs. Cordycepin markedly inhibited the activation of MMP-2 and -9 as well as the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in a dose-dependent manner in collagen type I-activated RaoSMCs. Moreover, cordycepin suppressed cycloxygenase-2 (COX-2) expression related to hyperplasia of RAoSMCs. Taken together, these data suggest that cordycepin may induce antiproliferation in RAoSMCs via the modulation of vessel wall remodeling. Therefore, cordycepin may be a potential therapeutic approach to treat restenosis.